Sixto-López Yudibeth, Gómez-Vidal José A, Correa-Basurto José
Laboratorio de Modelado Molecular y Diseño de Fármacos (Laboratory of Molecular Modeling and Drug Design), Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, 11340, Mexico.
Appl Biochem Biotechnol. 2014 Aug;173(7):1907-26. doi: 10.1007/s12010-014-0976-1. Epub 2014 Jun 3.
We describe the conformational behavior of histone deacetylase 8 (HDAC8) using molecular dynamics (MD) simulations. HDAC8 conformers were used for the docking studies using some known HDAC inhibitors (HDACi) suberoylanilide hydroxamic acid (SAHA), valproic acid (VPA), aroyl-pyrrole-hydroxy-amide (APHA-8) and tubacin to explore their interactions, binding modes, free energy values. The MD simulation show that HDAC8 make important surface changes at the catalytic site (CS) entrance as well as at two entrances locations in the 14-Å tunnel. In addition, we identify an alternate entrance to the 14-Å tunnel named adjacent to the catalytic site pocket (ACSP). By using docking studies, it was possible to elucidate the importance of hydrophobic and π-π interactions that are the most important for the ligand-HDAC8 complex structural stabilization. In conclusion, the ligand flexibility, molecular weight and chemical moieties (hydroxamic acid, aryl and aliphatic moieties) are the principal properties required to increase the binding affinity on HDAC8.
我们使用分子动力学（MD）模拟描述了组蛋白脱乙酰酶8（HDAC8）的构象行为。利用一些已知的组蛋白脱乙酰酶抑制剂（HDACi），如辛二酰苯胺异羟肟酸（SAHA）、丙戊酸（VPA）、芳酰基吡咯羟基酰胺（APHA - 8）和tubacin，将HDAC8构象异构体用于对接研究，以探索它们之间的相互作用、结合模式和自由能值。MD模拟表明，HDAC8在催化位点（CS）入口以及14埃通道的两个入口位置发生了重要的表面变化。此外，我们确定了一个与催化位点口袋相邻（ACSP）的14埃通道的备用入口。通过对接研究，有可能阐明疏水相互作用和π-π相互作用对于配体 - HDAC8复合物结构稳定的重要性。总之，配体的灵活性、分子量和化学基团（异羟肟酸、芳基和脂肪族基团）是提高与HDAC8结合亲和力所需的主要特性。
